Pheochromocytomas are rare but clinically important chromaffin cell tumors that constitute a surgically correctable cause of chronic hypertension. The clinical features and consequences of pheochromocytoma result from release of catecholamines (e.g., norepinephrine and epinephrine) by the tumor. We found that the measurement of plasma metanephrines is the most sensitive biochemical test to diagnose the tumor. In our studies of biochemical diagnosis to date, plasma metanephrines had a sensitivity of 99% and specificity of 90%. The new clonidine test coupled with the measurement of plasma metanephrines is the best test to rule out pheochromocytoma in patients presenting with symptoms that resemble the presence of the tumor. We also found that fluorodopamine positron emission tomography (PET) scanning improves the ability to localize a pheochromocytoma and it is superior to 131-I metaiodobenzylguanidine scintigraphy and Octreoscan. These findings justify 6-[18F]fluorodopamine PET scanning as a diagnostic tool. In addition, we are searching for any specific genetic or other markers to predict the course, malignant potential, and recurrence of pheochromocytoma. Inherited mutations of the RET protooncogene are tumorigenic in patients with multiple endocrine neoplasia type 2. However, it is not understood why only a few of the affected cells in the target organs develop into tumors. Genetic analysis of 9 pheochromocytomas from 5 unrelated patients with MEN 2 showed either duplication of the mutant RET allele in trisomy 10 or loss of the wild-type RET allele. Through either duplication of the mutant allele or loss of the wild-type allele, our results suggest a "second hit" causing a dominant effect of the mutant RET allele as a possible mechanism for pheochromocytoma tumorigenesis in patients with MEN 2. Finally, our laboratory is currently attempting to establish pheochromocytoma cell cultures and used new techniques such as microarray analysis to trace back phenotypic differences in tumors to underlying differences in gene expression and ultimately to the basic somatic or germline mutations responsible for the tumor. We also found that malignant and benign pheochromocytoma can be distinguished with high specificity and sensitivity based on a number of distinct serum protein patterns. We are also attemting to establish an animal model of metastatic pheochromocytoma. This will be done by testing subcutaneous, intraperitoneal, and intravenous injection of both human and mouse pheochromocytoma cells and screening the mice for the development of metastatic lesions in the lymph nodes, lungs, liver, and spleen. The long-range goal of this project is to develop effective treatments for pheochromocytoma.